A human relevance investigation of PPARα-mediated key events in the hepatocarcinogenic mode of action of propaquizafop in rats

Propaquizafop is an herbicide with demonstrated hepatocarcinogenic activity in rodents. A rodent-specific mode of action (MOA) in the liver via activation of peroxisome proliferator-activated receptor α (PPARα) has been postulated based on existing data. Experience with PPARα-inducing pharmaceuticals indicates a lack of human relevance of this MOA. The objective of the present investigation was to evaluate the dependency of early key events leading to liver tumors on PPARα activation in wildtype (WT) compared to PPARα-knockout (KO) rats following 2 weeks exposure to 75, 500 and 1000 ppm propaquizafop in the diet. In WT rats, both WY-14643 (50 mg/kg bw/day) and propaquizafop (dose-dependentl…